{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T07:04:42Z","timestamp":1763535882362,"version":"build-2065373602"},"reference-count":82,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-ONC\/29402\/2017, UIDP\/04138\/2020, UIDB\/04138\/2020, SFRH\/BD\/145522\/2019, and 2020.07115.BD."],"award-info":[{"award-number":["PTDC\/MED-ONC\/29402\/2017, UIDP\/04138\/2020, UIDB\/04138\/2020, SFRH\/BD\/145522\/2019, and 2020.07115.BD."]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer (BC) brain metastases is a life-threatening condition to which accounts the poor understanding of BC cells\u2019 (BCCs) extravasation into the brain, precluding the development of preventive strategies. Thus, we aimed to unravel the players involved in the interaction between BCCs and blood\u2013brain barrier (BBB) endothelial cells underlying BBB alterations and the transendothelial migration of malignant cells. We used brain microvascular endothelial cells (BMECs) as a BBB in vitro model, under conditions mimicking shear stress to improve in vivo-like BBB features. Mixed cultures were performed by the addition of fluorescently labelled BCCs to distinguish individual cell populations. BCC\u2013BMEC interaction compromised BBB integrity, as revealed by junctional proteins (\u03b2-catenin and zonula occludens-1) disruption and caveolae (caveolin-1) increase, reflecting paracellular and transcellular hyperpermeability, respectively. Both BMECs and BCCs presented alterations in the expression pattern of connexin 43, suggesting the involvement of the gap junction protein. Myosin light chain kinase and phosphorylated myosin light chain were upregulated, revealing the involvement of the endothelial cytoskeleton in the extravasation process. \u03b24-Integrin and focal adhesion kinase were colocalised in malignant cells, reflecting molecular interaction. Moreover, BCCs exhibited invadopodia, attesting migratory properties. Collectively, hub players involved in BC brain metastases formation were unveiled, disclosing possible therapeutic targets for metastases prevention.<\/jats:p>","DOI":"10.3390\/ijms22137057","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T10:03:19Z","timestamp":1625047399000},"page":"7057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood\u2013Brain Barrier Disruption"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8219-6240","authenticated-orcid":false,"given":"Joana","family":"Godinho-Pereira","sequence":"first","affiliation":[{"name":"iMed.ULisboa\u2014Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"given":"Ana Rita","family":"Garcia","sequence":"additional","affiliation":[{"name":"iMed.ULisboa\u2014Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-6883","authenticated-orcid":false,"given":"In\u00eas","family":"Figueira","sequence":"additional","affiliation":[{"name":"iMed.ULisboa\u2014Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Farm-ID\u2014Faculty of Pharmacy Association for Research and Development, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"given":"Rui","family":"Malh\u00f3","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculty of Sciences, Universidade de Lisboa, Campo Grande 016, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4649","authenticated-orcid":false,"given":"Maria Alexandra","family":"Brito","sequence":"additional","affiliation":[{"name":"iMed.ULisboa\u2014Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3322\/caac.21565","article-title":"Cancer treatment and survivorship statistics, 2019","volume":"69","author":"Kimberly","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41416-020-01161-4","article-title":"The lingering mysteries of metastatic recurrence in breast cancer","volume":"124","author":"Riggio","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.2174\/0929867326666190201113004","article-title":"Thioredoxin, glutathione and related molecules in tumors of the nervous system","volume":"27","author":"Branco","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_5","first-page":"683730","article-title":"Targeting the sanctuary site: Options when breast cancer metastasizes to the brain","volume":"33","author":"Krishnan","year":"2019","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1001\/jamaoncol.2017.0001","article-title":"Brain metastases in newly diagnosed breast cancer: A population-based study","volume":"3","author":"Martin","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.bbcan.2017.03.004","article-title":"Brain metastasization of breast cancer","volume":"1868","author":"Videira","year":"2017","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12943-018-0937-3","article-title":"The functional role of integrins during intra- and extravasation within the metastatic cascade","volume":"18","author":"Schumacher","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kang, S.A., Blache, C.A., Bajana, S., Hasan, N., Kamal, M., Morita, Y., Gupta, V., Tsolmon, B., Suh, K.S., and Gorenstein, D.G. (2016). The effect of soluble E-selectin on tumor progression and metastasis. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2366-2"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/boc.201500011","article-title":"Control of the blood-brain barrier function in cancer cell metastasis","volume":"107","author":"Blecharz","year":"2015","journal-title":"Biol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1242\/jcs.045112","article-title":"Cellular functions of FAK kinases: Insight into molecular mechanisms and novel functions","volume":"123","author":"Schaller","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13014-019-1230-3","article-title":"The increased adhesion of tumor cells to endothelial cells after irradiation can be reduced by FAK-inhibition","volume":"14","author":"Kouam","year":"2019","journal-title":"Radiat. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16408","DOI":"10.1038\/srep16408","article-title":"An EGFR\/Src-dependent \u03b24 integrin\/FAK complex contributes to malignancy of breast cancer","volume":"5","author":"Tai","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.devcel.2011.11.002","article-title":"VEGF-induced vascular permeability is mediated by FAK","volume":"22","author":"Chen","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1083\/jcb.201307067","article-title":"Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function","volume":"204","author":"Jean","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.brainresrev.2010.05.003","article-title":"Looking at the blood-brain barrier: Molecular anatomy and possible investigation approaches","volume":"64","author":"Cardoso","year":"2010","journal-title":"Brain Res. Rev."},{"key":"ref_17","first-page":"4","article-title":"Replicating the blood-brain barrier properties in an in vitro model: Effects of hydrocortisone and\/or shear stress","volume":"8","author":"Garcia","year":"2019","journal-title":"Arch. Anat."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cucullo, L., Hossain, M., Puvenna, V., Marchi, N., and Janigro, D. (2011). The role of shear stress in Blood-Brain Barrier endothelial physiology. BMC Neurosci., 12.","DOI":"10.1186\/1471-2202-12-40"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Figueira, I., Galego, S., Cust\u00f3dio-Santos, T., Vicente, R., Moln\u00e1r, K., Hask\u00f3, J., Malh\u00f3, R., Videira, M., Wilhelm, I., and Krizbai, I. (2021). Picturing breast cancer brain metastasis development to unravel molecular players and cellular crosstalk. Cancers, 13.","DOI":"10.3390\/cancers13040910"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.celrep.2014.07.050","article-title":"Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis","volume":"8","author":"Leong","year":"2014","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ccr.2013.05.008","article-title":"Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor","volume":"24","author":"Schumacher","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ccell.2017.07.001","article-title":"Intravascular survival and extravasation of tumor cells","volume":"32","author":"Strilic","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1111\/jcmm.14156","article-title":"Paracellular and transcellular migration of metastatic cells through the cerebral endothelium","volume":"23","author":"Herman","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s40478-019-0788-1","article-title":"Response of the neurovascular unit to brain metastatic breast cancer cells","volume":"7","author":"Fazakas","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/nrc3628","article-title":"Crossing the endothelial barrier during metastasis","volume":"13","author":"Reymond","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","first-page":"43","article-title":"Endothelial contractile cytoskeleton and microvascular permeability","volume":"2009","author":"Shen","year":"2009","journal-title":"Cell Health Cytoskelet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.canlet.2008.05.028","article-title":"Myosin light-chain kinase contributes to the proliferation and migration of breast cancer cells through cross-talk with activated ERK1\/2","volume":"270","author":"Zhou","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1242\/jcs.053793","article-title":"Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: A three-dimensional FRET study","volume":"123","author":"Khuon","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.neuron.2017.03.043","article-title":"Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis","volume":"94","author":"Andreone","year":"2017","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.2147\/OTT.S191317","article-title":"Caveolin-1: A multifaceted driver of breast cancer progression and its application in clinical treatment","volume":"12","author":"Qian","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1002\/jcp.27149","article-title":"Shear stress promotes anoikis resistance of cancer cells via caveolin-1-dependent extrinsic and intrinsic apoptotic pathways","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.abb.2018.03.029","article-title":"Tubeimoside V sensitizes human triple negative breast cancer MDA-MB-231 cells to anoikis via regulating caveolin-1-related signaling pathways","volume":"646","author":"Wang","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4932","DOI":"10.1158\/0008-5472.CAN-10-4249","article-title":"Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition","volume":"71","author":"Chiu","year":"2011","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12929-019-0497-x","article-title":"Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application","volume":"26","author":"Wu","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1096\/fj.201700699R","article-title":"Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure","volume":"32","author":"Johnson","year":"2018","journal-title":"FASEB J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.3892\/ijo.2017.4114","article-title":"Connexin 43 in the development and progression of breast cancer: What\u2019s the connection?","volume":"51","author":"Phillips","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3389\/fmed.2019.00192","article-title":"Connexin43 as a tumor suppressor: Proposed Connexin43 mRNA-circularRNAs-microRNAs axis towards prevention and early detection in breast cancer","volume":"6","author":"AbouHaidar","year":"2019","journal-title":"Front. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R522","DOI":"10.1186\/bcr1042","article-title":"Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture","volume":"7","author":"Pollmann","year":"2005","journal-title":"Breast Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrm.2016.80","article-title":"Tight junctions: From simple barriers to multifunctional molecular gates","volume":"17","author":"Zihni","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/med.21270","article-title":"Myosin light chain kinase signaling in endothelial barrier dysfunction","volume":"33","author":"Rigor","year":"2013","journal-title":"Med. Res. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3718","DOI":"10.1158\/1078-0432.CCR-14-2021","article-title":"Molecular pathways: Endothelial cell FAK\u2014A target for cancer treatment","volume":"22","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"679","DOI":"10.18632\/oncotarget.1459","article-title":"P-cadherin signals through the laminin receptor alpha6beta4 integrin to induce stem cell and invasive properties in basal-like breast cancer cells","volume":"5","author":"Vieira","year":"2014","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.00238.2015","article-title":"Tumor cell intravasation","volume":"311","author":"Chiang","year":"2016","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6304701","DOI":"10.1155\/2018\/6304701","article-title":"Survival Mechanisms and influence factors of circulating tumor cells","volume":"2018","author":"Wang","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.cell.2014.07.013","article-title":"Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis","volume":"158","author":"Aceto","year":"2014","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"0210051","DOI":"10.1115\/1.4035121","article-title":"The mechanics of single cell and collective migration of tumor cells","volume":"139","author":"Lintz","year":"2017","journal-title":"J. Biomech. Eng."},{"key":"ref_47","first-page":"5301","article-title":"An emerging tumor invasion mechanism about the collective cell migration","volume":"11","author":"Yang","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3940","DOI":"10.1038\/s41467-019-11963-7","article-title":"Misshapen coordinates protrusion restriction and actomyosin contractility during collective cell migration","volume":"10","author":"Plutoni","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Khalil, A.A., Ilina, O., Vasaturo, A., Venhuizen, J.-H., Vullings, M., Venhuizen, V., Bilos, A., Figdor, C., Span, P.N., and Friedl, P. (2019). Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1. bioRxiv, Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/2019.12.30.888958v1.full.","DOI":"10.1101\/2019.12.30.888958"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1039\/c3ib40149a","article-title":"Mechanisms of tumor cell extravasation in an in vitro microvascular network platform","volume":"5","author":"Chen","year":"2013","journal-title":"Integr. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.cell.2020.08.045","article-title":"Regulation of collective metastasis by nanolumenal signaling","volume":"183","author":"Wrenn","year":"2020","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/path.4304","article-title":"Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain","volume":"232","author":"Avraham","year":"2014","journal-title":"J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1016\/j.febslet.2006.06.056","article-title":"Involvement of Rho\/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells","volume":"580","author":"Li","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1007\/s10439-015-1517-y","article-title":"Quantification of malignant breast cancer cell MDA-MB-231 transmigration across brain and lung microvascular endothelium","volume":"44","author":"Fan","year":"2016","journal-title":"Ann. Biomed. Eng."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Weidert, E., Pohler, S.E., Gomez, E.W., and Dong, C. (2014). Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanomainduced endothelial cell-cell junction disassembly. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108092"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1242\/jcs.047522","article-title":"Mechanisms for transcellular diapedesis: Probing and pathfinding by \u2018invadosome-like protrusions\u2019","volume":"122","author":"Carman","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s12031-011-9629-9","article-title":"The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles","volume":"46","author":"Deng","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2353\/ajpath.2006.050429","article-title":"Caveolin-1 deficiency (\u2212\/\u2212) conveys premalignant alterations in mammary epithelia, with abnormal lumen formation, growth factor independence, and cell invasiveness","volume":"168","author":"Sotgia","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1152\/physrev.00046.2003","article-title":"Role of caveolae and caveolins in health and disease","volume":"84","author":"Cohen","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00401-007-0274-x","article-title":"Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood\u2013brain barrier breakdown","volume":"114","author":"Nag","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Arvanitis, C., Khuon, S., Spann, R., Ridge, K.M., and Chew, T.L. (2014). Structure and biomechanics of the endothelial transcellular circumferential invasion array in tumor invasion. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089758"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1053\/j.gastro.2009.03.040","article-title":"Nuclear myosin II regulates the assembly of preinitiation complec for ICAM-1 gene transcription","volume":"137","author":"Li","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"47586","DOI":"10.18632\/oncotarget.9896","article-title":"Increased cancer stem cell invasion is mediated by myosin IIB and nuclear translocation","volume":"7","author":"Thomas","year":"2016","journal-title":"Oncotarget"},{"key":"ref_64","first-page":"904","article-title":"Role of connexins in metastatic breast cancer and melanoma brain colonization","volume":"126","author":"Stoletov","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Elzarrad, M.K., Haroon, A., Willecke, K., Dobrowolski, R., Gillespie, M.N., and Al-Mehdi, A.B. (2008). Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med., 6.","DOI":"10.1186\/1741-7015-6-20"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.taap.2017.11.020","article-title":"Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers","volume":"338","author":"Tsai","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E83","DOI":"10.1038\/ncb0402-e83","article-title":"Sensing the environment: A historical perspective on integrin signal transduction","volume":"4","author":"Miranti","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10555-008-9165-4","article-title":"Signal transduction by focal adhesion kinase in cancer","volume":"28","author":"Zhao","year":"2009","journal-title":"Cancer Metastasis Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.mvr.2011.09.011","article-title":"Endothelial FAK as a therapeutic target in disease","volume":"83","author":"Infusino","year":"2012","journal-title":"Microvasc. Res."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Guo, X., Eitnier, R.A., Beard, R.S., Meegan, J.E., Yang, X., Aponte, A.M., Wang, F., Nelson, P.R., and Wu, M.H. (2020). Focal adhesion kinase and Src mediate microvascular hyperpermeability caused by fibrinogen-\u03b3C-terminal fragments. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231739"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1113\/jphysiol.2001.013289","article-title":"Modulatory role of focal adhesion kinase in regulating human pulmonary arterial endothelial barrier function","volume":"539","author":"Mehta","year":"2002","journal-title":"J. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6090","DOI":"10.1128\/MCB.25.14.6090-6102.2005","article-title":"Targeted deletion of the integrin \u03b24 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kB, causing defects in epidermal growth and migration","volume":"25","author":"Nikolopoulos","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2748","article-title":"Integrins in cancer: Biological implications and therapeutic opportunities","volume":"10","author":"Desgrosellier","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/labinvest.2015.82","article-title":"Clinical significance of the integrin alpha6beta4 in human malignancies","volume":"95","author":"Stewart","year":"2015","journal-title":"Lab. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1007\/s10495-013-0860-4","article-title":"Phosphorylation and nuclear translocation of integrin \u03b24 induced by a chemical small molecule contribute to apoptosis in vascular endothelial cells","volume":"18","author":"Ge","year":"2013","journal-title":"Apoptosis"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Pel\u00e1ez, R., Pariente, A., P\u00e9rez-Sala, A., and Larrayoz, I.M. (2019). Integrins: Moonlighting proteins in invadosome formation. Cancers, 11.","DOI":"10.3390\/cancers11050615"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1083\/jcb.201702184","article-title":"Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells","volume":"217","author":"Genna","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1002\/1873-3468.12215","article-title":"Activation of focal adhesion kinase through an interaction with \u03b24 integrin contributes to tumorigenicity of colon cancer","volume":"590","author":"Tai","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"H3190","DOI":"10.1152\/ajpheart.01177.2006","article-title":"Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress","volume":"292","author":"Colgan","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_80","first-page":"1293","article-title":"Ethanol enhances basal and flow-stimulated nitric oxide synthase activity in vitro by activating an inhibitory guanine nucleotide binding protein","volume":"289","author":"Hendrickson","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3389\/fimmu.2019.00711","article-title":"PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-cell diapedesis across the blood-brain barrier during neuroinflammation","volume":"10","author":"Wimmer","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1002\/eji.201546251","article-title":"Postarrest stalling rather than crawling favors CD8+ over CD4+ T-cell migration across the blood-brain barrier under flow in vitro","volume":"46","author":"Rudolph","year":"2016","journal-title":"Eur. J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7057\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:23:59Z","timestamp":1760163839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":82,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22137057"],"URL":"https:\/\/doi.org\/10.3390\/ijms22137057","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,6,30]]}}}